The ability to test hypotheses in a variety of neuroscience fields has exploded due to the new ability to monitor and manipulate key cellular events in living animals and other models of disease and neuronal function in a high throughput fashion using modern cell biological approaches. Our previous award provided the foundation for a world-class Neuroscience Core, in support of NINDS-funded aims of UCSD Neuroscientists. With this application, we seek to incorporate high-throughput and high-sensitivity approaches in our established Neuroscience Imaging Core through purchase and active management of new equipment for our Major Users. Furthermore, we aim to increase the number NINDS-funded investigators participating in this initiative from 8 to 28 labs, to reflect ou outstanding cellular neuroscience community and number of qualifying projects. The University of California, San Diego Neurosciences Core has grown to be a centerpiece for research within the neuroscience community. Its existence has resulted in remarkable yields in productivity, expanded scientific scope and ability to test hypotheses using cutting edge technology and in vivo approaches. In this application, we propose move into exciting new areas through: 1. In vivo brain imaging of live neural tissue with high-sensitivity multiphoton microscopy. 2. High throughput electron microscopic ultrastructural imaging taking advantage of the latest breakthroughs in serial block face scanning electron microscopy (SBFSEM) and emergent probe technologies developed at UCSD. 3. More than tripling the number of Major User NINDS-funded investigators at UCSD. The research that this equipment will support involves neuronal stem cell differentiation, migration, axonal guidance, activity-dependent plasticity, connectivity, injury repair, degenerative disease and developmental biology. The requested systems were chosen because of their high data quality, unsurpassed abilities to document events in the nervous system not previously possible, and their ease of use, which is critical for a multi-user Core. The Neuroscience Core offers on-hand technicians to provide training for each of the services provided. The Core leverages the expertise of the other UCSD efforts including the National Center for Microscopy and Imaging Research (NCMIR), which will provide expertise and staff to meet the proposed goals to support training and research. The flexibility, dynamic range, sensitivity, and processing capabilities that will be provided by these tools is essential fr the next phase of the NINDS-funded work that has important implications for multiple nervous system diseases.